Sandweiss Alexander J, Cottier Karissa E, McIntosh Mary I, Dussor Gregory, Davis Thomas P, Vanderah Todd W, Largent-Milnes Tally M
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, USA.
School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, USA.
Oncotarget. 2017 Dec 9;8(69):114109-114122. doi: 10.18632/oncotarget.23141. eCollection 2017 Dec 26.
Test the putative contribution of 17-β-estradiol in the development of spreading depression (SD) events and head pain in awake, non-restrained rats.
Female, Sprague-Dawley rats were intact or underwent ovariectomy followed one week later by surgery to place electrodes onto the dura to detect epidural electroencephalographic activity (dEEG). dEEG activity was recorded two days later for 12 hours after systemic administration of 17-β-estradiol (180 μg/kg, i.p.). A separate set of rats were observed for changes in exploratory, ambulatory, fine, and rearing behaviors; periorbital allodynia was also assessed.
A bolus of 17-β-estradiol significantly elevated serum estrogen levels, increased SD episodes over a 12-hour recording period and decreased rearing behaviors in ovariectomized rats. Pre-administration of ICI 182,780, an estrogen receptor antagonist, blocked 17-β-estradiol-evoked SD events and pain behaviors; similar results were observed when the antimigraine therapeutic sumatriptan was used.
These data indicate that an estrogen receptor-mediated mechanism contributes to SD events in ovariectomized rats and pain behaviors in both ovariectomized -and intact- rats. This suggests that estrogen plays a different role in each phenomenon of migraine where intense fluctuations in concentration may influence SD susceptibility. This is the first study to relate estrogen peaks to SD development and pain behaviors in awake, freely moving female rats, establishing a framework for future preclinical migraine studies.
检测17-β-雌二醇在清醒、未束缚大鼠中对扩散性抑制（SD）事件及头痛发生发展中的假定作用。
雌性Sprague-Dawley大鼠分为完整组或去卵巢组，去卵巢组在一周后进行手术，将电极置于硬脑膜上以检测硬膜外脑电图活动（dEEG）。全身注射17-β-雌二醇（180μg/kg，腹腔注射）两天后记录12小时的dEEG活动。另一组大鼠观察其探索、行走、精细动作及竖毛行为的变化；同时评估眶周痛觉过敏情况。
单次注射17-β-雌二醇显著提高血清雌激素水平，增加去卵巢大鼠在12小时记录期内的SD发作次数，并减少其竖毛行为。预先给予雌激素受体拮抗剂ICI 182,780可阻断17-β-雌二醇诱发的SD事件及疼痛行为；使用抗偏头痛治疗药物舒马曲坦时也观察到类似结果。
这些数据表明雌激素受体介导的机制参与了去卵巢大鼠的SD事件以及去卵巢和完整大鼠的疼痛行为。这表明雌激素在偏头痛的每种现象中发挥不同作用，其中雌激素浓度的剧烈波动可能影响SD易感性。这是第一项将雌激素峰值与清醒、自由活动雌性大鼠的SD发展及疼痛行为相关联的研究，为未来的临床前偏头痛研究建立了框架。
